Regulatory regions of rat insulin I gene necessary for expression in transgenic mice

Dandoy-Dron, Françoise; Monthioux, Eliane; Jami, Jacques; Bucchini, Danielle

doi:10.1093/nar/19.18.4925

Cited by 35 publications

(37 citation statements)

References 34 publications

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“…The truncated and hemaglutinin-tagged dominant-negative Foxo1 allele (DNFoxo) (23) was a generous gift from D. Accili (Columbia University, New York, NY). It was inserted into a RIP-I/␤-globin expression vector (24,25), sequenced, and microinjected into fertilized eggs of C57BL/6 ϫ CBA mice according to standard protocol of the Mouse Genetics Core of the Washington University School of Medicine. Nine founders were obtained, of which five passed the transgene through germline transmission, as evidenced by genotyping and backcrossing to C57BL/6J mice (The Jackson Laboratory).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Foxo1 Protects Pancreatic Islet β-Cells Against Fatty Acid and Endoplasmic Reticulum Stress–Induced Apoptosis

et al. 2008

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OBJECTIVE—β-Cells are particularly susceptible to fatty acid–induced apoptosis associated with decreased insulin receptor/phosphatidylinositol-3 kinase/Akt signaling and the activation of stress kinases. We examined the mechanism of fatty acid–induced apoptosis of mouse β-cells especially as related to the role played by endoplasmic reticulum (ER) stress–induced Foxo1 activation and whether decreasing Foxo1 activity could enhance cell survival. RESEARCH DESIGN AND METHODS—Mouse insulinoma (MIN6) cells were administered with fatty acids, and the role of Foxo1 in mediating effects on signaling pathways and apoptosis was examined by measuring Foxo1 activity and using dominant-negative Foxo1. RESULTS—Increasing fatty acid concentrations (100–400 μmol/l palmitate or oleate) led to early Jun NH2-terminal kinase (JNK) activation that preceded induction of ER stress markers and apoptosis. Foxo1 activity was increased with fatty acid administration and by pharmacological inducers of ER stress, and this increase was prevented by JNK inhibition. Fatty acids induced nuclear localization of Foxo1 at 4 h when Akt activity was increased, indicating that FoxO1 activation was not mediated by JNK inhibition of Akt. In contrast, fatty acid administration for 24 h was associated with decreased insulin signaling. A dominant-negative Foxo1 adenovirus (Adv-DNFoxo) conferred cells with protection from ER stress and fatty acid–mediated apoptosis. Microarray analysis revealed that fatty acid induction of gene expression was in most cases reversed by Adv-DNFoxo, including the proapoptotic transcription factor CHOP (C/EBP [CCAAT/enhancer binding protein] homologous protein). CONCLUSIONS—Early induction of JNK and Foxo1 activation plays an important role in fatty acid–induced apoptosis. Expressing a dominant-negative allele of Foxo1 reduces expression of apoptotic and ER stress markers and promotes β-cell survival from fatty acid and ER stress, identifying a potential therapeutic target for preserving β-cells in type 2 diabetes.

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Section: Methodsmentioning

confidence: 99%

Inhibition of Foxo1 Protects Pancreatic Islet β-Cells Against Fatty Acid and Endoplasmic Reticulum Stress–Induced Apoptosis

et al. 2008

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“…Transgenic mice expressing HuIFN␤ under the control of the rat insulin I promoter (18) in outbred albino CD-1 background (CD-1 RIP-HuIFN␤) were generated by backcrossing the original C57BL6/SJL RIP-HuIFN␤ transgenic mice to CD-1 mice (14). NOD mice, NOR mice, and NOD-SCID mice, unable to produce mature T and B lymphocytes (19), were obtained from The Jackson Laboratory (Bar Harbor, ME).…”

Section: Micementioning

confidence: 99%

IFNβ Accelerates Autoimmune Type 1 Diabetes in Nonobese Diabetic Mice and Breaks the Tolerance to β Cells in Nondiabetes-Prone Mice

Alba

Puertas

Carrillo

et al. 2004

The Journal of Immunology

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Genetic and environmental factors are decisive in the etiology of type 1 diabetes. Viruses have been proposed as a triggering environmental event and some evidences have been reported: type I IFNs exist in the pancreata of diabetic patients and transgenic mice expressing these cytokines in β cells develop diabetes. To determine the role of IFNβ in diabetes, we studied transgenic mice expressing human IFNβ in the β cells. Autoimmune features were found: MHC class I islet hyperexpression, T and B cells infiltrating the islets and transfer of the disease by lymphocytes. Moreover, the expression of β2-microglobulin, preproinsulin, and glucagon in the thymus was not altered by IFNβ, thus suggesting that the disease is caused by a local effect of IFNβ, strong enough to break the peripheral tolerance to β cells. This is the first report of the generation of NOD (a model of spontaneous autoimmune diabetes) and nonobese-resistant (its homologous resistant) transgenic mice expressing a type I IFN in the islets: transgenic NOD and nonobese-resistant mice developed accelerated autoimmune diabetes with a high incidence of the disease. These results indicate that the antiviral cytokine IFNβ breaks peripheral tolerance to β cells, influences the insulitis progression and contributes to autoimmunity in diabetes and nondiabetes- prone mice.

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“…This change in ATP sensitivity is similar in magnitude to changes observed with Kir6.2 mutations associated with NDM in humans (2). To investigate the effect of mutant K ATP channels with altered ATP sensitivity on insulin release in pancreatic ␤-cells, the NH 2 -terminal truncated subunit, Kir6.2[⌬N2- 30], was fused at the COOH-terminus with the GFP and cloned downstream of the RIP I in order to drive expression specifically in pancreatic ␤-cells (23). From Ͼ400 injected embryos, PCR analysis identified seven founder mice that were bred with C57Bl/6 mice to establish seven founder lines (lines A-G).…”

Section: Resultsmentioning

confidence: 99%

Expression of ATP-Insensitive KATP Channels in Pancreatic β-Cells Underlies a Spectrum of Diabetic Phenotypes

et al. 2006

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Glucose metabolism in pancreatic ␤-cells elevates cytoplasmic [ATP]/[ADP], causing closure of ATP-sensitive K؉ channels (K ATP channels), Ca 2؉ entry through voltage-dependent Ca 2؉ channels, and insulin release. Decreased responsiveness of K ATP channels to the [ATP]/[ADP] ratio should lead to decreased insulin secretion and diabetes. We generated mice expressing K ATP channels with reduced ATP sensitivity in their ␤-cells. Previously, we described a severe diabetes, with nearly complete neonatal lethality, in four lines (A-C and E) of these mice. We have now analyzed an additional three lines (D, F, and G) in which the transgene is expressed at relatively low levels. These animals survive past weaning but are glucose intolerant and can develop severe diabetes. Despite normal islet morphology and insulin content, islets from glucose-intolerant animals exhibit reduced glucose-stimulated insulin secretion. The data demonstrate that a range of phenotypes can be expected for a reduction in ATP sensitivity of ␤-cell K ATP channels and provide models for the corollary neonatal diabetes in humans. Diabetes

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Regulatory regions of rat insulin I gene necessary for expression in transgenic mice

Cited by 35 publications

References 34 publications

Inhibition of Foxo1 Protects Pancreatic Islet β-Cells Against Fatty Acid and Endoplasmic Reticulum Stress–Induced Apoptosis

Inhibition of Foxo1 Protects Pancreatic Islet β-Cells Against Fatty Acid and Endoplasmic Reticulum Stress–Induced Apoptosis

IFNβ Accelerates Autoimmune Type 1 Diabetes in Nonobese Diabetic Mice and Breaks the Tolerance to β Cells in Nondiabetes-Prone Mice

Expression of ATP-Insensitive KATP Channels in Pancreatic β-Cells Underlies a Spectrum of Diabetic Phenotypes

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